D. Joanne Lynn, MD

DESCRIPTION

Wilson's disease (WD) is an inherited disorder of copper metabolism with a wide spectrum of system involvement (also known as hepatolenticular degeneration). CNS manifestations include dystonia and psychiatric symptomatology. Other organs prominently affected include the liver and kidneys.

EPIDEMIOLOGY

Incidence

Estimates of prevalence vary widely (10–30 per million), with a heterozygous carrier rate of 1 in 90.

Prevalence

The average worldwide prevalence has been estimated to be 30 per million.

RISK FACTORS

Genetics

WD is inherited as an autosomal recessive disease due to the mutation of the ATPase ATP7B gene on chromosome 13. The risk of WD is 40% in a sibling of an index case and 0.5% in a child of an index patient.

GENERAL PREVENTION

Since this is a rare disorder, prevention efforts focus on identification of affected family members and prevention of organ injury once an index patient is identified.

PATHOPHYSIOLOGY

The ATP7B gene codes for a metal-transporting P-type ATPase which is primarily expressed on hepatocytes. It functions in the transmembrane transport of copper within hepatocytes. In WD, decreased ATP7B protein leads to decreased transport of copper into the bile and resultant hepatic copper accumulation and injury. Decreased ATP7B protein function is also associated with decreased incorporation of copper into ceruloplasmin (protein synthesized by liver which is the major carrier of copper in the blood). Copper eventually spills into the bloodstream and is abnormally deposited into various organs including brain, kidney, and cornea, causing tissue damage.

ETIOLOGY

Genetic – autosomal recessive disorder caused by mutations of the ATP7B gene on chromosome 13.

COMMONLY ASSOCIATED CONDITIONS

• Hepatic
  • Chronic active hepatitis
  • Cirrhosis
  • Fulminant hepatic failure
• Hematologic
  • Coombs-negative hemolytic anemia
  • Hypersplenism
  • Coagulopathy due to liver disease
• Renal
  • Fanconi's syndrome
  • Urolithiasis
  • Hematuria
  • Proteinuria
  • Peptiduria
  • Nephrocalcinosis
• Ophthalmologic
  • Sunflower cataracts
  • Night blindness
• Other
  • Osteopenia
  • Cardiomyopathy/cardiac arrhythmias
  • Arthritis
  • Amenorrhea
  • Hypoparathyroidism

HISTORY

• Neurologic symptoms of WD generally present later than hepatic manifestations – typically in the third decade although pediatric neurologic presentations of WD do occur. Neurologic presentations include bulbar symptoms such as dysarthria and difficulty swallowing, dystonia, and a wide spectrum of neuropsychiatric manifestations. Patients may give a history of deteriorating handwriting or micrographia.
• The spectrum of hepatic presentations of WD includes acute hepatitis or liver failure, cirrhosis, or isolated splenomegaly due to portal hypertension associated with occult cirrhosis. Coombs-negative hemolytic anemia may be associated with acute liver and/or renal failure. Transient episodes of jaundice may occur due to hemolysis.

Pediatric Considerations

Many children are without symptoms but hepatic enlargement or elevated serum transaminases may be found incidentally. Early subtle findings in pediatric patients may include behavioral changes, deterioration in school performance, or poor hand–eye coordination.

PHYSICAL EXAM

The classic triad of WD is cirrhosis, neurologic manifestations, and Kayser–Fleischer (KF) pigmented corneal rings but the majority of patients with WD do not have all of these presenting conditions. Common neurologic findings include tremor, motor incoordination, dysarthria, dystonia, and spasticity. Dysautonomia and pseudobulbar palsy with dysphagia may be present. Psychiatric manifestations may include depression, anxiety, and psychosis. Seizures are rare.

DIAGNOSTIC TESTS AND INTERPRETATION

Lab

Initial Lab Tests

• Serum aminotransaminase levels
• Serum ceruloplasmin (level <200 mg/L consistent with WD, but it is an acute phase reactant, so levels may be falsely normal with inflammatory states)
• Serum non-ceruloplasmin bound copper level often elevated above 25 µg/dL in untreated patients
• 24-hour urine copper (usually >100 µg/24 hours in WD but lesser amounts can still be consistent with diagnosis)
• Slit-lamp examination

Follow-Up & Special Considerations

Interpretation of many laboratory tests for WD can be obscured by other conditions.

Imaging

Brain MRI frequently shows hyperintensity of the basal ganglia on T2 imaging. Other abnormal findings may include abnormal signal of the gray and white matter, cerebellar hemispheres, and the dorsal and central regions of the pons. Generalized and focal atrophy and ventricular dilation may also be present.

Initial Approach

MRI should be obtained in all patients with neurologic WD prior to initiation of treatment.

Follow-Up & Special Considerations

The diagnosis of WD in patients who present with hepatic disease is more complex. Because no single test establishes the diagnosis, a combination of laboratory features is required to firmly establish the diagnosis.

Diagnostic Procedures/Other

• Slit-lamp ophthalmologic examination for KF rings: Despite a clinical tradition that KF rings must be present once neuropsychiatric signs are present in WD, there are reports of a small percentage of patients with neuropsychiatric signs without KF rings.
• Hepatic copper content via liver biopsy is increased in most patients with WD, typically >250 µg/g dry weight. Other hepatic diseases can be associated with increased hepatic copper.

Pathological Findings

The lenticular nuclei of the brain grossly appear brown due to copper deposition. Early pathology includes astrocytic proliferation. Necrosis, gliosis, and cystic changes later develop in the thalamus, brainstem, cerebellum, and cerebral cortex. The KF ring is caused by copper deposition in Descemet's membrane.

DIFFERENTIAL DIAGNOSIS

• Huntington's disease
• Essential tremor
• Parkinson's disease
• Neurologic complications of chronic hepatic encephalopathy
• Multiple sclerosis

MEDICATION

First Line

• The primary treatment approach to WD is to remove copper from the various tissues and to prevent reaccumulation. Copper-chelating agents are the first-line medications for WD therapy. Penicillamine (dimethylcysteine), the traditional mainstay of WD treatment, avidly chelates copper; the complexed copper is excreted in urine. The traditional dosage is 1–2 g/day PO but many recommend starting with 250–500 mg/day and increasing by 250 mg increments every 4–7 days to a maximum of 1,000–1,500 mg/day in 2–4 divided dosages. Penicillamine should be administered 1 hour before or 2 hours after a meal as food inhibits its absorption. The usual maintenance dose is 750–1,000 mg/day in 2 divided doses. Pediatric dosing is 20 mg/kg/day in 2 or 3 divided doses.
• Zinc acetate or zinc sulfate interferes with uptake of dietary copper from the GI tract. It should be administered at a dose of 50 mg elemental zinc 3 times per day on an empty stomach. It has been used as first-line therapy for asymptomatic and presymptomatic WD.

Second Line

• Trientine (triethylenetetramine dihydrochloride) is another copper chelation therapy. It should be taken on an empty stomach. A typical daily dose is 750–2,000 mg in 3 divided doses. Trientine is less toxic than penicillamine, but it has been associated with lupus nephritis and sideroblastic anemia.
• Ammonium tetrathiomolybdate (TM) is an experimental therapy which complexes copper in the GI tract to prevent absorption and in the bloodstream to reduce tissue deposition. TM is administered in a regimen of 6 doses daily: 3 with meals and 3 between meals, at starting doses of 20 mg gradually titrated upward (20–60 mg/dose). TM is associated with reversible bone marrow depression and hepatotoxicity.

ADDITIONAL TREATMENT

General Measures

Patients are initially treated with decoppering agents, zinc, and dietary restriction. After several years of therapy, stable patients may be treated with lower maintenance doses of a chelating agent or zinc alone.

Issues for Referral

Individual multidisciplinary specialty approaches are needed to improve quality and longevity of patients. Dietary counseling is necessary. Various specialist referrals may be required dependent upon disease manifestations (neurologist, hepatologist, hematologist, etc.).

Additional Therapies

Serum and hepatic vitamin E levels are often low in WD. Symptomatic improvement has been reported with supplemental vitamin E but no rigorous studies are available.

SURGERY/OTHER PROCEDURES

Orthoptic hepatic transplantation is recommended for patients with progressive liver failure unresponsive to chelation therapy or acute liver failure due to fulminant hepatitis. Hepatic transplantation results in improvement of neuropsychiatric symptoms.

IN-PATIENT CONSIDERATIONS

Initial Stabilization

Patients who present with acute inflammatory hepatic or neurologic disease or one of the other potential organ involvements of WD may require hospitalization.

Admission Criteria

Admission is required if symptoms are life-threatening (e.g., hepatic failure) or if hydration, mobility, or nutrition is compromised.

FOLLOW-UP RECOMMENDATIONS

Patient Monitoring

Blood counts and urinalysis should be followed closely during penicillamine therapy because hypersensitivity reactions are not uncommon. Copper concentrations in 24-hour urine collections can be used to guide titration of therapy. A 24-hour cupriuresis may exceed 1,000 µg immediately after starting treatment; during maintenance treatment, urinary copper excretion should be around 200–500 µg/day.

DIET

Dietary copper restriction is not recommended as the primary therapy but is an important component of disease management. Foods with high copper content, such as shellfish, nuts, chocolate, mushrooms, and organ meats, should be avoided. Water in households with copper content should be assessed for copper content and copper containers/cookware should not be used for food.

PATIENT EDUCATION

• Compliance with long-term chelation therapy must be encouraged because rapid deterioration has been reported after abrupt discontinuation of penicillamine.
• Wilson Disease Organization. Website: www.wilsonsdisease.org

PROGNOSIS

Symptomatic WD patients require chronic lifelong therapy. Interrupted or inadequate therapy may lead to death, most often due to hepatic failure. If treatment is begun in a timely fashion, most patients will become asymptomatic or nearly so. Residual dystonia and dysarthria are often seen in neurologic cases. Long-term follow-up and monitoring is required to ensure adequate treatment.

COMPLICATIONS

• Initiation of treatment with decoppering agents can be associated with a worsening of neurologic deficits which may require discontinuation of treatment. This is most frequent with penicillamine.
• Penicillamine: Adverse events include fever, rash, proteinuria, lupus-like reaction, thrombocytopenia, leukopenia, gastritis, hepatotoxicity. Each of the decoppering agents is associated with additional potential risks.

• Das SK, Ray K. Wilson's disease: an update. Nat Clin Pract Neurol 2006;2:482–493.
• Roberts EA, Schilsky ML. Diagnosis and treatment of Wilson disease: an update. Hepatology 2008;47(6):2089–2111.
• USDA National Nutrient Database. Listing of copper content in various foods. Available at http://www.ars.usda.gov/Services/docs.htm?docid=17477. Accessed on May 30, 2011.

ICD9

275.1 Disorders of copper metabolism

First-degree relatives of an index patient with WD should be screened for WD. No single laboratory assessment is sufficient. Mutation analysis is the only reliable screening tool. Disease symptoms may be prevented in presymptomatic patients identified through family screening by treatment with chelating agents and/or zinc.